Although mu opioid receptor agonists are the most commonly used opioids for the treatment of moderate to severe pain in the clinic, the side effects of mu opioids such as constipation, respiratory depression, pruritus, abuse liability, and physical dependence limit their value as a medication. Research to identify novel opioids without these side effects is pivotal to advance the health care of humans. Scientists have discovered N/OFQ, a heptadecapeptide that is an endogenous ligand for the novel opioid receptors (now named NOP receptors). The amino acid sequence of the NOP receptor has close homology to each of the classical, well-characterized mu, kappa, delta opioid receptors, but ligands that bind to these classical opioid receptors do not bind to NOP receptors with high affinity. The actions of N/OFQ have much in common with those of opioid peptides at the cellular level. Nevertheless, the behavioral effects of various NOP receptor agonists with different affinity and efficacy have not been systematically studied in primates. The studies proposed in this project will test the hypothesis that functions/behavioral effects of NOP receptors are independent of classical opioid receptors and activation of NOP receptors produces antinociception with fewer side effects and reduced abuse liability in monkeys. In the proposed studies, a variety of physiological and behavioral endpoints will be measured and receptor-selective agonists and antagonists will be used to investigate the functions of NOP receptors. Dose-response curves, time course of each agent, and possible side effects (e.g., scratching, sedation, respiratory depression, cardiovascular changes) will be thoroughly investigated. Proposed studies will help determine whether NOP receptor agonists represent a novel class of opioids that produce analgesia but have fewer side effects in primates. Behavioral effects of NOP receptor agonists will be systematically compared with those of mu opioid analgesics across different, well-established functional/behavioral assays in monkeys. In particular, the therapeutic margin of safety of NOP agonists will be determined in the monkey behavioral models. Our proposed studies, with an emphasis on behavioral effects in the whole organism, are the first attempt to elucidate the functions of NOP receptors in monkeys. These basic studies of behavioral neuropharmacology will establish a valuable translational foundation for understanding of biobehavioral functions of NOP receptors and future research and development of NOP receptor agonists in humans.